Project Summary Biological sex is associated with clear differences in HIV immunopathogenesis, but there is limited understanding of the mechanisms of this variation. There are 19.1 million women and girls living with HIV infection, accounting for slightly more than half of the people living with HIV globally, but women are generally a minority of study participants and sex-stratified analyses are uncommon. Transgender women bear a disproportionate burden of infection, and even fewer studies have sought to understand the biological impact of female gender identity on HIV infection outcomes. Studies of sex and gender differences in the mechanistic pathways driving immune responses to infection, pathologic inflammation and control of the HIV reservoir are critical to the development of novel therapeutic interventions. In this proposal, we investigate both biological sex and female gender identity to disentangle their contributions to immune pathology. Specifically, we will work with the extensive genomic and clinical data in the International Collaboration for the Genomics of HIV (ICGH) dataset to analyze genetic determinants of HIV disease progression on the sex chromosomes and in a sex stratified analysis of the autosomes. We will also work with the Transcendendo cohort in Brazil, a cohort designed with community input to follow individuals assigned a male sex at birth and living with a female gender. We will design groups for the collection of biospecimens from cohort participants selected based on differing use of gender-affirming hormone therapy, HIV infection status, and accounting for critical covariates including trauma and depression. With immune transcriptional profiling, we will assess the impact of gender identity on immune activation profiles, to inform the understanding of the unique contributions of chromosomal sex, hormone use and lived gender identity. Finally, we will specifically test the sex-differential impact of estrogen signaling on T cell activation and HIV latency reversal, building on our prior studies identifying sex specific characteristics of the HIV latent reservoir. Combined these studies, will provide novel insights into the impact of both sex and gender on the immune response to HIV infection.